Recarbrio
imipenem, cilastatin and relebactam
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity. Two dose-dependent toxicities with clinical relevance were CNS toxicity primarily in rats and minimal kidney toxicity primarily in monkeys.”
Why that species
In vitro and in vivo metabolic profiles and satisfactory pharmacokinetics; monkey previously used for imipenem/cilastatin
“The selection was based on the in vitro and in vivo metabolic profiles and the demonstration of satisfactory pharmacokinetics in these species. The monkey had previously been used as the non-rodent species for the assessment of toxicological profile of imipenem/cilastatin including the evaluation of renal toxicity caused by imipenem.”
Surrogate molecule
No surrogate; relebactam itself was tested, alone and with imipenem/cilastatin
“Relebactam was evaluated in repeat-dose toxicity studies in rats (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase) and in monkeys (4 weeks with 4 weeks recovery, and 12 weeks with no recovery phase).”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and monkey)
“In 1- and 3-month repeated-dose toxicology studies, relebactam produced only limited toxicity.”
Pivotal GLP studies
Up to 3-month rat and monkey studies of relebactam, plus a monkey combination study with imipenem/cilastatin
“The program includes repeat-dose studies up to 3 months exposure in rats and monkeys, and a repeat dose combination study with REL and imipenem/relebactam.”
Route in tox
Intravenous
“The intravenous (IV) route of administration was utilized in all toxicology studies (except in the first phase of the juvenile study in rat and the EFD study in mouse) to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Relebactam negative in Ames, chromosomal aberration and rat bone marrow micronucleus assays
“Relebactam was shown to be negative for mutagenicity and/or clastogeniceffects in an Ames assay, a chromosomal aberration study, and in vivo in a rat bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (non-genotoxic, short treatment duration)
“In the absence of genotoxicity, and as the proposed treatment duration is relatively short, no carcinogenicity tests have been conducted.”
Reproductive & developmental
Mouse, rat and rabbit EFD: external/skeletal malformations (incl. cleft palate) in mice only; none in rats or rabbits
“In rats and rabbits, malformations and variations were not increased by relebactam above concurrent or historical control levels. However, in mice, increases in specificexternal and/or skeletal alterations were observed.”
Safety pharmacology
Monkey telemetry: no effects on blood pressure, heart rate, ECG/QTc, respiration or body temperature
“No MK-7655-related changes compared to vehicle control values were observed for blood pressure measurements, heart rate, electrocardiogram parameters including QTc intervals, respiratory parameters, or body temperature.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Recarbrio don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure (FDA multi-discipline review, p. 41)
NOAEL / key findings
CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure
“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Low brain, lens and bone levels in rat QWBA; relebactam not prone to cross the blood-brain barrier
“Brain, seminal vesicles, eye lens and bone were among the tissues with lowest concentrations of radioactivity (<1.5 μg equiv/g at Tmax). The low levels of radioactivity in the brain suggests REL is not prone to pass the blood brain barrier.”
Modality-specific risk
CNS toxicity (rat) and renal toxicity (monkey), possibly additive with imipenem
“Because nonclinical studies with relebactam revealed a potential for CNS toxicity in rats and renal toxicity in monkeys, it may be important to determine if an additive or synergisticpotential for these toxicities can occur when imipenem/cilastatin are clinically administered concomitantly with relebactam.”